Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models

Tan, Fenlai; Yang, Guiqun; Wang, Yanping; Chen, Haibo; Yu, Bo; Li, He; Guo, Jing; Huang, Xiaoling; Deng, Yi-Fang; Yu, Peilin; Ding, Lieming

doi:10.1016/j.biopha.2017.12.073

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…While some researchers assumed that inhibition of EGFR, VEGF or VEGFR would represent a new therapeutic approach for psoriasis [10], some disagreements occurred.…”

Section: Discussionmentioning

confidence: 99%

Remission of Psoriasis during Treatment with Apatinib in a Patient with Rectal Cancer

Chong¹,

Ge²,

Li³

et al. 2019

J Dermatol Res Ther

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Psoriasis is a chronic, recurrent inflammatory skin disease characterized by abnormal keratinocyte proliferation and vascular hyperplasia. Apatinib is a tyrosine kinase inhibitor which has been reported to be effective in some tumors thought to be associated with inhibition of the proliferation of endothelial cells by selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2). We present a 54-yearold patient with a 30-year history of psoriasis, who did not respond well to oral treatment with acitretin in combination with topical corticosteroids. The patient was diagnosed with rectal cancer and was treated with oral apatinib 250 mg once daily. To our surprise, all the psoriasis lesions were completely resolved after a 53-days course of treatment. Although apatinib and its variants have been extensively used as an anticancer drug, there is no report of their use in psoriasis. As with other antitumor treatments, we speculate that apatinib is effective for psoriasis owing to an inhibition of endothelial cell growth in psoriasis lesions. This observation suggests that apatinib may be a useful drug to treat psoriasis in the future and deserves further investigation in its own right.

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“…While some researchers assumed that inhibition of EGFR, VEGF or VEGFR would represent a new therapeutic approach for psoriasis [10], some disagreements occurred.…”

Section: Discussionmentioning

confidence: 99%

Remission of Psoriasis during Treatment with Apatinib in a Patient with Rectal Cancer

Chong¹,

Ge²,

Li³

et al. 2019

J Dermatol Res Ther

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“…Icotinib, a small-molecule EGFR tyrosine kinase inhibitor, is the first-line treatment for advanced NSCLC. Based on the fact that the EGFR signaling pathway plays an important role in the development of psoriasis [14, 15], here we reported the pharmacokinetics, safety, and preliminary efficacy of icotinib cream in Chinese psoriasis patients. Although the circulating concentration of icotinib increased in a dose-dependent manner, the pharmacokinetic data showed that the overall system exposure was still very low, which was even lower than 1% of a single oral dose of 100mg icotinib tablet (healthy subjects orally received 100 mg icotinib hydrochloride tablets for a single oral dose; related C max , 719 ± 206 ng/mL; AUC, 3361 ± 703 h.ng/mL).…”

Section: Discussionmentioning

confidence: 99%

“…Epidermal growth factor receptor (EGFR) plays a critical role in the growth and proliferation of epidermal cells and participates in the excessive proliferation and differentiation of psoriatic keratinocytes [14, 15]. Besides, the downstream signal molecules of EGFR, including the Erk, Akt, and Stat families, are expressed and phosphorylated at significantly higher levels in psoriasis lesions than in nonlesioned areas or normal skin [16, 17], which indicates that the downstream signals of EGFR were also closely related to the development of psoriasis.…”

Section: Introductionmentioning

confidence: 99%

“…Icotinib is a small-molecule EGFR tyrosine kinase inhibitor [18–20]. Preclinical studies [14] showed that icotinib hydrochloride could specifically inhibit EGFR tyrosine kinase and block the activation of downstream signaling pathways of Stat3 and Akt, regulating the proliferation and differentiation of keratinocytes and inhibiting angiogenesis and further improving the pathological conditions of epidermal keratosis and fine epidermis in psoriasis. A previous phase I clinical study (NCT02574091) demonstrated that icotinib cream at 1% and 2% concentrations was well tolerated by both healthy subjects and psoriasis subjects.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and Safety of Icotinib Hydrochloride Cream in Patients with Mild to Moderate Chronic Plaque Psoriasis: A Randomized Double-Blind Vehicle-Controlled Phase 1 Study

Liu

Lou

Zhou

et al. 2019

BioMed Research International

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Objective.This phase I study aimed to systematically assess the safety, local tolerability, pharmacokinetics, and preliminary efficacy of topical icotinib hydrochloride cream in patients with mild to moderate plaque psoriasis.Materials and Methods.Eligible Chinese adult patients with mild to moderate psoriasis were assigned to the icotinib cream or vehicle group. Icotinib cream with increasing concentrations (0.5%, 1.0%, 2.0%, and 4.0%) or vehicle were administered by the fingertip unit method to the skin lesions twice a day for 4 weeks. Safety assessments included the incidence and severity of adverse events (AEs), local tolerability at the treatment area, vital signs, and laboratory examinations. Plasma levels of icotinib were also measured for the pharmacokinetics calculation. The efficacy was preliminarily explored by assessing the improvement in the severity level using Target Plaque Severity Score (TPSS) and overall improvement using the Psoriasis Area Severity Index (PASI) and Dermatological Quality Life Index.Results.Forty-one patients were enrolled and qualified for safety analysis. 27 (65.9%) patients experienced at least one AE, of which application-site adverse drug reactions (ADRs) were reported in 6 (14.6%) patients. All ADRs were of grade 1 or 2, most common irritation (4.5%), itching (3.1%), and erythema (2.4%), and resolved during follow-up. The systemic exposure to icotinib was very low; the highest plasma concentration was 0.214 ng/mL, while the area under the curve from 0 to 12 hours was 1.626 h·ng/mL. The TPSS improved for all icotinib groups after treatment in a dose- and time-dependent manner.Conclusion.This phase 1 study demonstrated favorable safety, tolerable toxicity, and preliminary efficacy of icotinib cream in patients with mild to moderate psoriasis. The dose concentration of 2.0% (twice daily based on the fingertip unit method) is recommended for further study.Study Design.This is a single-center, randomized, double-blind, and vehicle-controlled study.

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“…It has been demonstrated to have improved efficacy and better safety in patients with nonsmall cell lung cancer (Liu et al, ). In addition, icotinib has also been found to alleviate psoriasis symptoms effectively (Tan et al, ).…”

Section: Introductionmentioning

confidence: 99%

Validation of an LC‐MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study

Xiao

Maiolino

Yan

et al. 2018

Biomedical Chromatography

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In this study, a simple and sensitive LC-MS/MS method was developed and validated for simultaneous determination of icotinib and its four circulating metabolites in human plasma. The analytes were extracted with acetonitrile and separated on a C column using 2 mm ammonium acetate containing 0.2% formic acid and acetonitrile as mobile phase. The analytes were introduced into the mass spectrometer via an electrospray ionization source operated in positive ion mode. Precursor-to-product transitions were optimized to be m/z 392.2 → 304.1 for icotinib, m/z 424.1 → 278.2 for M1 and M2, m/z 408.2 → 320.1 for M3, m/z 410.2 → 322.1 for M4 and m/z 394.4 → 278.1 for IS. The assay showed good linearity over the concentration ranges of 0.1-600 ng/mL for icotinib and 0.1-200 ng/mL for metabolites, with correlation coefficients >0.994 (r > 0.994). The LLOQ was 0.1 ng/mL for each analyte. The intra- and inter-day precisions (RSD) were ≤12.98% while the accuracy (RE) ranged from -8.76 to 12.01%. No significant matrix effect was observed. The validated method was successfully applied for the pharmacokinetic study of icotinib and its four circulating metabolites in human plasma after oral administration of icotinib at a single dose of 125 mg.

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Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models

Cited by 11 publications

References 30 publications

Remission of Psoriasis during Treatment with Apatinib in a Patient with Rectal Cancer

Remission of Psoriasis during Treatment with Apatinib in a Patient with Rectal Cancer

Pharmacokinetics and Safety of Icotinib Hydrochloride Cream in Patients with Mild to Moderate Chronic Plaque Psoriasis: A Randomized Double-Blind Vehicle-Controlled Phase 1 Study

Validation of an LC‐MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study

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